Raf-1 sets the threshold of Fas sensitivity by modulating Rok-a signaling

Autor(en)

Daniela Piazzolla, Katrin Meissl, Lucia Kucerova, Cristina Rubiolo, Manuela Baccarini

Abstrakt

Ablation of the Raf-1 protein causes fetal liver apoptosis, embryonic lethality, and selective hypersensitivity to Fas-induced cell death. Furthermore, Raf-1-deficient cells show defective migration as a result of the deregulation of the Rho effector kinase Rok-a. In this study, we show that the kinase-independent modulation of Rok-a signaling is also the basis of the antiapoptotic function of Raf-1. Fas activation stimulates the formation of Raf-1-Rok-a complexes, and Rok-a signaling is up-regulated in Raf-1-deficient cells. This leads to increased clustering and membrane expression of Fas, which is rescued both by kinase-dead Raf-1 and by interfering with Rok-a or its substrate ezrin. Increased Fas clustering and membrane expression are also evident in the livers of Raf-1-deficient embryos, and genetically reducing Fas expression counteracts fetal liver apoptosis, embryonic lethality, and the apoptotic defects of embryonic fibroblasts. Thus, Raf-1 has an essential function in regulating Fas expression and setting the threshold of Fas sensitivity during embryonic life. ΠThe Rockefeller University Press.

Organisation(en)

Department für Biochemie und Zellbiologie

Externe Organisation(en)

Max F. Perutz Laboratories GmbH (MFPL), Cell Med Research GmbH

Journal

The Journal of Cell Biology (JCB)

Band

171

Seiten

1013-1022

Anzahl der Seiten

10

ISSN

0021-9525

Publikationsdatum

2005

Peer-reviewed

Ja

ÖFOS 2012

1060 Biologie

Link zum Portal

https://ucrisportal.univie.ac.at/de/publications/raf1-sets-the-threshold-of-fas-sensitivity-by-modulating-roka-signaling(49801834-e396-4f9f-a7d4-66ac6eff2acb).html